EP0768302B1 - Hydroxypyridinone - Google Patents

Hydroxypyridinone Download PDF

Info

Publication number
EP0768302B1
EP0768302B1 EP96810622A EP96810622A EP0768302B1 EP 0768302 B1 EP0768302 B1 EP 0768302B1 EP 96810622 A EP96810622 A EP 96810622A EP 96810622 A EP96810622 A EP 96810622A EP 0768302 B1 EP0768302 B1 EP 0768302B1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
methyl
benzyloxy
pyridin
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP96810622A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP0768302A3 (de
EP0768302A2 (de
Inventor
Paul Zbinden
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH
Novartis AG
Original Assignee
Novartis Pharma GmbH Austria
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Pharma GmbH Austria, Novartis AG filed Critical Novartis Pharma GmbH Austria
Priority to SA96170399A priority Critical patent/SA96170399B1/ar
Publication of EP0768302A2 publication Critical patent/EP0768302A2/de
Publication of EP0768302A3 publication Critical patent/EP0768302A3/de
Application granted granted Critical
Publication of EP0768302B1 publication Critical patent/EP0768302B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/04—Chelating agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, unsubstituted lower alkoxycarbonyl, amino, lower alkylamino, di-lower alkylamino, aminocarbonyl, N-lower alkylaminocarbonyl, N, N-di-lower alkylaminocarbonyl, carboxyl, unsubstituted lower alkylsulfonyl, aminosulfonyl, cyano, hydroxy, nitro, tetrazolyl, or lower alkylenedioxy with group B forms a heterocyclic oxygen-containing ring system;
  • R 2 is hydrogen, lower alkyl which is unsubstituted or substituted by halogen, hydroxy or trifluoromethyl, lower alkylene hydroxy, lower alkylene-lower alkoxy, unsubstituted lower alkylenecarboxy, unsubstituted lower alkylenecarbonyl-lower
  • EP-A-0 494 754, WO 94 03169 A, EP-A-0 335 745 and EP-A-0 325 559 are hydroxypyridine derivatives which is derived from the compounds of formula I by the group B of the formula I differ.
  • WO 96 22021 A describes 3-hydroxypyridin-4-one derivatives as protein hydroxylation inhibitors, which for the treatment of fibrotic or fibroproliferative diseases can be used.
  • Halogen is z. As chlorine, bromine or fluorine, but may also mean iodine.
  • Lower alkyl and lower alkylene are straight-chain or branched. For yourself, such as Lower alkyl, or as part of other groups, such as. B. lower alkoxy, lower alkylamine, Lower alkylaminocarbonyl, lower alkylene hydroxy, they may be unsubstituted or substituted be with halogen, hydroxy, or trifluoromethyl, preferably they are unsubstituted or substituted with hydroxy.
  • Methylene may be unsubstituted or substituted with lower alkyl, halogen or hydroxy, preferably it is unsubstituted or substituted with hydroxy.
  • Lower alkyl is z.
  • Lower alkoxy is z.
  • n -Propoxy isopropoxy, n- butoxy, isobutoxy, sec- butoxy, tert- butoxy, n -amyloxy, isoamyloxy, preferably methoxy and ethoxy.
  • Lower alkoxycarbonyl is z. B. lower alkyl-OC (O) -, z. B. n -propoxycarbonyl, isopropoxycarbonyl, n- butoxycarbonyl, sec- butoxycarbonyl, tert- butoxycarbonyl, preferably methoxycarbonyl and ethoxycarbonyl.
  • Lower alkylamino is, for example, n- propylamino, n- butylamino, i- propylamino, i- butylamino, preferably methylamino and ethylamino
  • Diniederalkylamino is, for example, dimethylamino, diethylamino, di- n- propylamino, n- butylamino, di- n- butylamino, n- propyl n- butylamino, preferably dimethylamino, diethylamino and methylethylamino.
  • Aminocarbonyl refers to the carbamoyl radical
  • N-lower alkylaminocarbonyl is e.g. N-methylcarbamoyl, N-ethylcarbamoyl, Nn -propylcarbamoyl, N-isopropylcarbamoyl, preferably N-methylcarbamoyl and N-ethylcarbamoyl.
  • N, N-di-lower alkylaminocarbonyl is, for example, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N, N-di- n- propylcarbamoyl, N-methyl-N-isopropylcarbamoyl, preferably N, N- Dimethylcarbamoyl, N, N -diethylcarbamoyl and N-methyl-N-ethylcarbamoyl.
  • Lower alkylene by itself or as part of other groups such.
  • Lower alkyleneamine, lower alkylenecarboxy, lower alkanoyloxy-lower alkylene represents the group - (CH 2 ) n -, wherein n is a natural number from and having 1 to and having 7, preferably from and having 1 to and 4, and is, for example, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene.
  • Lower alkylenedioxy refers to the group -O- (CH 2 ) n -O-, where n is a natural number from and with 1 to and with 7, and is e.g. Methylenedioxy, 1,2-ethylenedioxy, 1,3- n- propylenedioxy, preferably methylenedioxy and 1,2-ethylenedioxy.
  • Lower alkylene hydroxy represents the group - (CH 2 ) n -OH, wherein n is a natural number from and having 1 to and having 7, preferably from and having 1 to and having 4, and is, for example, methylene hydroxy, ethylene hydroxy, propylene hydroxy, in particular however, ethylene hydroxy and propylene hydroxy.
  • Lower alkylene-lower alkoxy is lower alkylene hydroxy etherified with lower alkyl, e.g. B methoxymethylene, Methoxyethylene, ethoxymethylene, ethoxyethylene, in particular ethoxyethylene, while lower alkanoyloxy lower alkyl is lower alkylene hydroxy substituted with lower alkanoyl esterified, z.
  • lower alkanoyloxy lower alkyl is lower alkylene hydroxy substituted with lower alkanoyl esterified, z.
  • Lower alkylene carboxy represents the group wherein n is a natural number of from and having 1 to and having 7, preferably from and having 1 to and having 4, and is, for example, methylenecarboxy, ethylenecarboxy, propylenecarboxy, butylenecarboxy, primarily methylenecarboxy, ethylenecarboxy or propylenecarboxy, while lower alkylenecarbonyl-lower alkoxy with lower alkyl esterified Niederalkylencarboxy is, for.
  • Methyl ethylenecarboxylate ethylenecarboxylic acid ethylester, propylenecarboxylic acid methylester, propylenecarboxylic acid ethylester, butylenecarboxylic acid methylester, butylenecarboxylic acid ethylester, especially ethylenecarboxylic acid ethylester, propylenecarboxylic acid ethylester or butylenecarboxylic acid ethylester.
  • Lower alkyleneamine is the group - (CH 2 ) n -NH 2 , where n is a natural number from and with 1 to and with 7, preferably from and with 1 to and with 4, and is, for example, methyleneamine, ethyleneamine, propyleneamine, Butyleneamine, but also for radicals in which one or two hydrogens on the nitrogen are replaced by lower alkyl, preferably N-methyl-lower alkylene amine, N, N-dimethyl-lower alkylene amine, N-ethyl-lower alkylene amine, N, N-di-lower alkyleneamine, N-methyl-N-ethyl-lower alkylene amine.
  • N-lower alkanoyl-lower alkyleneamine is one of the nitrogen-bonded Hydrogen of Niederalkylenamins replaced by a lower alkanoyl radical, z.
  • Lower alkanoyl is z. As acetyl, propanoyl, butanoyl but also formyl.
  • Formyl-lower alkylene represents the group wherein n is a natural number of from and having 1 to and having 7, preferably from and having 1 to and having 4, and is, for example, ethylene aldehyde, propylene aldehyde, butylene aldehyde, especially ethylene aldehyde.
  • Lower alkoxycarbonyl means the group wherein m is a natural number from and with 0 to and with 6, preferably from and with 0 to and with 3, and is especially methyloxycarbonyl.
  • Oxygenated heterocyclic rings are saturated or unsaturated rings of five to and with seven ring members of which at least one is oxygen and where appropriate one or more further heteroatoms, for example nitrogen, are present, so z.
  • dioxolane dioxane, oxazole, oxazine, optionally one or more Ring carbon atoms are oxidized to carbonyl, such as.
  • dioxanone, oxazolone, oxazinone may be unsubstituted or substituted, in particular unsubstituted or substituted with lower alkyl, lower alkoxy or hydroxy.
  • Aryl is phenyl or naphthyl which is substituted or unsubstituted.
  • Aryl is preferably phenyl, which is unsubstituted or substituted by one or more, in particular one or two, substituents, for example, lower alkyl, lower alkoxy, hydroxy, nitro, amino, halogen, trifluoromethyl, Carboxy, amino or cyano, is substituted.
  • substituents for example, lower alkyl, lower alkoxy, hydroxy, nitro, amino, halogen, trifluoromethyl, Carboxy, amino or cyano, is substituted.
  • aryl means unsubstituted Phenyl or naphthyl, or phenyl represented by lower alkyl, lower alkoxy, hydroxy, Halogen or trifluoromethyl substituted.
  • Heteroaryl is an aromatic radical having 5 to and having 7 ring atoms, wherein at least one the ring atom is a heteroatom, e.g. Pyrrolyl, furanyl, thiophenyl, pyridyl, pyranyl, pyrimidinyl.
  • Azaheteroaryl is preferred, which means that at least one of the ring atoms is a Is nitrogen atom.
  • Azaheteroaryl may contain other ring heteroatoms, z. Nitrogen, Oxygen or sulfur; it is z.
  • pyrrolyl pyridyl, pyrimidinyl or pyrazinyl.
  • Heteroaryl may be substituted or unsubstituted.
  • heteroaryl which is unsubstituted or by one or more, in particular one or two, substituents lower alkyl, Halogen or trifluoromethyl substituted.
  • heteroaryl means unsubstituted Pyridyl.
  • Radicals such as pyrrolyl, pyridyl, pyrimidinyl and pyrazinyl can be attached via a ring nitrogen atom or a ring carbon atom, radicals such as pyridyl or pyrimidinyl are preferably bound via a C atom.
  • Salts of compounds of formula I are especially pharmaceutically acceptable salts, especially salts with bases, such as corresponding alkali metal or alkaline earth metal salts, for.
  • bases such as corresponding alkali metal or alkaline earth metal salts
  • salts with bases such as corresponding alkali metal or alkaline earth metal salts, for.
  • sodium, potassium or magnesium salts pharmaceutically acceptable transition metal salts such as zinc or copper salts
  • salts with ammonia or organic amines such as cyclic amines such as mono-, di- or Triniederalkylaminen such as Hydroxyniederalkylaminen, z.
  • B mono-, di- or Trihydroxyniederalkylaminen, hydroxy lower alkyl lower alkyl amines or Polyhydroxyniederalkylaminen. Cyclic amines are for.
  • morpholine As morpholine, thiomorpholine, piperidine or pyrrolidine.
  • suitable mono-lower alkylamines are ethyl- and tert- butylamine, as di-lower alkylamines, for example diethyl- and diisopropylamine, and, for example, trimethyl- and triethylamine as tri-lower alkylamines.
  • Corresponding Hydroxyniederalkylamine are z.
  • mono-, di- and triethanolamine; Hydroxyniederalkyl-lower alkyl amines are z.
  • N, N-dimethylamino and N, N-diethylaminoethanol as polyhydroxy lower alkylamine comes z.
  • acid addition salts for example with strong inorganic acids such as mineral acids, eg. As sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, eg. As acetic acid, such as optionally unsaturated dicarboxylic acids, eg. As malonic, maleic or fumaric acid, or as hydroxycarboxylic acids, eg. As tartaric acid or citric acid, or with sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, eg.
  • strong inorganic acids such as mineral acids, eg. As sulfuric acid, a phosphoric acid or a hydrohalic acid
  • strong organic carboxylic acids such as lower alkanecarboxylic acids, eg. As acetic acid, such as optionally unsaturated dicarboxylic acids, eg. As malonic, maleic or fumaric acid, or as
  • methane or p- toluenesulfonic acid are formed.
  • Compounds of formula I with an acidic group, for. Carboxy, and a basic group, e.g. As amino, may also be in the form of internal salts, ie in zwitterionic form, or it may be a part of the molecule as an inner salt, and another part as a normal salt. Also included are unsuitable for pharmaceutical uses salts, since these can be used for example for the isolation or purification of free compounds I and their pharmaceutically acceptable salts.
  • the compounds of the formula I have valuable pharmacological properties, in particular pronounced binding of trivalent metal ions, in particular those of iron (AE Martell and RJ Motekaitis, "Determination and Use of Stability Constants", VCH Publishers, New York 1992). You can, such as. In the animal model using the non-iron-overloaded bile fistula rat (RJ Bergeron et al., J. Med. Chem., 34 , 2072-2078 (1991); GF Smith, WH McCurdy and H.
  • iron (III) ions In various diseases of warm-blooded animals, in particular of humans, there is an excess of iron (III) ions in the blood and deposition of iron-containing pigments in the tissue, eg.
  • iron (III) ions Fe 3+ ions
  • thalassemia, sickle cell anemia, sideroblastic anemia, aplastic anemia, and other anemic forms in which hemosiderosis (ie, a local or general increase in iron stores in otherwise undamaged body tissues) play a role.
  • This type also includes morbid conditions that develop in patients after multiple blood transfusions or repeated dialysis treatment in the absence or damaged kidney function.
  • a reduction in the iron (III) concentration is also of interest for the treatment of diseases caused by iron (III) -dependent microorganisms and parasites, which is of fundamental importance not only in human medicine, in particular in malaria, but also in veterinary medicine.
  • the complex formation with other trivalent metals can be used for their excretion from the organism, eg. As for the removal of aluminum in dialysis encephalopathy and osteomalacia, as well as in Alzheimer's disease
  • Desferrioxamine B has long been known and used therapeutically for these purposes (H. Bickel, H. Keberle and E. Vischer, Helv. Chim. Acta 46 , 1385-9 [1963]).
  • H. Bickel, H. Keberle and E. Vischer, Helv. Chim. Acta 46 , 1385-9 [1963] As a disadvantage of this preparation, however, turns out the fact that desferrioxamine and its salts on oral administration have only a low, inadequate efficacy and in all the above applications require a parenteral administration form. So z.
  • it is recommended as a particularly effective method to administer the drug by means of a slow (8 to 12 hours) subcutaneous infusion but this requires the use of a portable mechanical device such as an infusion syringe actuated by electric drive.
  • the present invention thus provides compounds of formula I, which are both by their excellent oral effectiveness and by their tolerability even at high dosage.
  • the invention relates to the compounds of formula I, wherein R 1 is hydrogen, halogen, lower alkyl, unsubstituted lower alkoxycarbonyl, amino, unsubstituted lower alkylamino, unsubstituted di-lower alkylamino, aminocarbonyl, N-lower alkylaminocarbonyl, N, N-di-lower alkylaminocarbonyl, carboxyl, cyano, hydroxy, nitro or lower alkylenedioxy, which is a heterocyclic oxygen-containing ring system with the group B.
  • R 1 is hydrogen, halogen, lower alkyl, unsubstituted lower alkoxycarbonyl, amino, unsubstituted lower alkylamino, unsubstituted di-lower alkylamino, aminocarbonyl, N-lower alkylaminocarbonyl, N, N-di-lower alkylaminocarbonyl, carboxyl, cyano,
  • R 2 is hydrogen, lower alkyl which is unsubstituted or substituted by halogen, hydroxy or trifluoromethyl, lower alkylene hydroxy, lower alkylene-lower alkoxy, unsubstituted lower alkylenecarboxy, unsubstituted lower alkylenecarbonyl-lower alkoxy, lower alkyleneamine, or N-lower alkanoyl-lower alkylene amine;
  • R 3 is hydrogen, lower alkyl, carboxyl, lower alkanoyloxy lower alkyl or N-lower alkylaminocarbonyl;
  • R 4 is hydrogen; An unsubstituted or substituted with lower alkyl, halogen or hydroxy methylene, carbonyl or together with R 2 and the atoms bonded to them an oxygen-containing heterocyclic ring; and
  • B is mono- or polysubstituted or unsubstituted phenyl or naphthyl or mono- or polysubstituted or
  • the invention relates to the compounds of formula I, wherein R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, cyano, hydroxy or nitro; R 2 is unsubstituted or substituted by halogen, hydroxy or trifluoromethyl lower alkyl, lower alkylene or lower alkyleneamine; R 3 and R 4 are hydrogen; A is unsubstituted or substituted by lower alkyl, halogen or hydroxy methylene, carbonyl or together with R 2 and the atoms bonded to them an unsubstituted oxygen-containing heterocyclic ring; and B is simply substituted or unsubstituted phenyl or naphthyl or monosubstituted or unsubstituted heteroaryl; mean; and their stereoisomers, tautomers and pharmaceutically acceptable salts, wherein, unless otherwise stated, lower alkyl and lower alkylene may alternatively be substituted with halogen, hydroxy or trifluoromethyl by themselves
  • the invention relates to the compounds of formula I, wherein R 1 is hydrogen, halogen or unsubstituted lower alkyl; R 2 is unsubstituted or halogen, hydroxy or trifluoromethyl substituted lower alkyl or lower alkylene hydroxy; R 3 and R 4 are hydrogen; A is unsubstituted or substituted by lower alkyl, halogen or hydroxy methylene or together with R 2 and the atoms bonded to them an unsubstituted oxygen-containing heterocyclic ring; and B is simply substituted or unsubstituted phenyl or naphthyl or monosubstituted or unsubstituted heteroaryl; mean; and their stereoisomers, tautomers and pharmaceutically acceptable salts, wherein, unless otherwise stated, lower alkyl and lower alkylene may alternatively be substituted with halogen, hydroxy or trifluoromethyl by themselves or as part of other groups.
  • the invention relates to the specific compounds described in the examples and salts thereof.
  • the invention 3-hydroxy-1- (2-hydroxy-ethyl) -2- (hydroxy-phenylmethyl) -1 H -pyridin-4-one, 3-hydroxy-1- (2-hydroxy-ethyl) relates - 2- (4-methyl-benzyl) -1 H -pyridin-4-one; 3-Hydroxy-1- (2-hydroxy-ethyl) -2- (hydroxy-methyl-4-fluorophenyl) -1 H -pyridin-4-one; 3-Hydroxy-1- (2-hydroxy-ethyl) -2- (4-fluoro-benzyl) - 1H -pyridin-4-one; 3-Hydroxy-1- (2-hydroxy-ethyl) -2- (hydroxy-4-chlorophenyl-methyl) -1 H -pyridin-4-one; 3-Hydroxy-1- (2-hydroxy-ethyl) -2- (4-chlorobenzyl) - 1H -pyridin-4-one; and
  • the process corresponds to the known reaction of 3-hydroxypyran-4-ones with ammonia or primary amines.
  • hydroxy groups may be in the form of an easily cleavable ester or ether group, preferably an alkanoyl or aralkanoyl ester group or a cycloheteroalkyl, Aralkyl or Alkoxyalkylether distr, but also a silyl ester or Silylether distr especially as acetyl or benzoyl esters or as tetrahydropyranyl, benzyl or methoxymethyl ether.
  • an easily cleavable ester or ether group preferably an alkanoyl or aralkanoyl ester group or a cycloheteroalkyl, Aralkyl or Alkoxyalkylether distr, but also a silyl ester or Silylether distr especially as acetyl or benzoyl esters or as tetrahydropyranyl, benzyl or methoxymethyl ether.
  • the reaction between the pyranone of formula II and the amine of formula III takes place without solvents or in suitable inert polar solvents, in particular monohydric or polyhydric alcohols, e.g. B. lower alkanols or lower alkane polyols, such as Methanol, propanol, isopropanol, glycol, propanediol, or especially ethanol, ethylene glycol or diethylene glycol.
  • suitable inert polar solvents in particular monohydric or polyhydric alcohols, e.g. B. lower alkanols or lower alkane polyols, such as Methanol, propanol, isopropanol, glycol, propanediol, or especially ethanol, ethylene glycol or diethylene glycol.
  • a base, z. B. a tertiary amine from Advantage.
  • the reaction takes place at room temperature or at elevated temperatures, preferably between room temperature and the reflux temperature of the reaction mixture.
  • the temperature can also be increased or decreased during the reaction period.
  • the starting materials of the formula II are novel and also the subject of the present invention. They can be prepared by methods known per se by reaction of pyromic acid [CAS registry no. : 496-63-9 ] or suitable derivatives with the corresponding aryl or heteroaryl aldehydes and, if necessary, subsequent introduction of suitable protective groups, and, if appropriate, by further derivatization by methods known per se.
  • compounds of the formula II are obtained by reacting pyromic acid with an aldehyde of the formula V wherein R 1 and B have the meaning given under formula I, in a conventional manner in ethanolic sodium hydroxide solution and then, if desired, introduces suitable protecting groups, such.
  • the 3-hydroxy function is etherified with an aralkyl halide in a conventional manner and protects the exocyclic hydroxy function with a Cycloheteroalkylether.
  • the cleavage of the protecting groups, which are not part of the desired end product of Formula I are carried out in a conventional manner, for. B. by solvolysis, in particular hydrolysis, Alcoholysis or acidolysis, or by reduction, especially hydrogenolysis or chemical reduction, optionally in stages or simultaneously.
  • a compound of formula I, wherein A is hydroxymethylidene be oxidized to the corresponding carbonyl compound, to obtain a compound of formula I, wherein A is carbonyl.
  • the reaction is carried out, for example, in an inert non-polar solvent, such as a halo-lower alkane, with the addition of a bisalkanesulfoxide and a pyridine-SO 3 complex.
  • a compound of formula I, wherein A is hydroxymethylidene may, for. B. also for corresponding alkane be reduced to give a compound of formula I, where A is methylene.
  • the compound is first acylated and then in the presence of a catalyst, e.g. B. palladium, reacted with hydrogen.
  • R 2 and A together with the atoms to which they are attached form an oxygen-containing azaheterocycle.
  • starting compounds of formula I or any intermediates interfering reactive groups e.g. As carboxy, hydroxy or amino groups may contain these are temporarily protected by easily removable protective groups. advantageously, however, you can also for the implementation of a suitable intermediate of Use formula IV.
  • Starting materials and intermediates may be in pure form, for example after Workup, as last mentioned, in partially purified form or even, for example, directly be used as crude products
  • the compounds, including their salts, may also be in the form of hydrates or solvates can be obtained, or their crystals can z.
  • B. used for crystallization Include solvent.
  • Solvents and diluents are, for example, water, alcohols, eg. B. lower alkanols, such as methanol, ethanol, propanol or butanol, diols, such as ethylene glycol, tri- or polyols, such as glycene or diethylene glycol, or aryl alcohols, such as phenol or benzyl alcohol, Acid amides, e.g. As carboxamides, such as N, N-dimethylformamide, or N, N-dimethylacetamide, Amides of inorganic acids such as hexamethylphosphoric triamide, ethers, e.g. B.
  • alcohols eg. B. lower alkanols, such as methanol, ethanol, propanol or butanol
  • diols such as ethylene glycol, tri- or polyols, such as glycene or diethylene glycol
  • aryl alcohols such as phenol
  • cyclic Ethers such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethly ethers, halogenated hydrocarbons, such as halo-lower alkanes, z. Methylene chloride or chloroform, ketones such as acetone, nitriles such as acetonitrile, esters, such as ethyl acetate, bisalkanesulfoxides such as dimethyl sulfoxide, nitrogen heterocycles, such as N-methylpyrrolidone or pyridine, hydrocarbons, e.g. B.
  • such starting materials are preferably used and intermediates, each in free form or in salt form, which are among the Initially described as particularly valuable compounds I or their salts.
  • New starting materials and intermediates, each in free or salt form, for the Preparation of the compounds I or their salts, their use and processes for their Production also form an object of the invention.
  • the invention also relates to those embodiments of the method in which one from a compound obtainable as an intermediate at any stage of the process starting and performing the missing process steps, or in which a starting material formed under the reaction conditions or in the form of a derivative, for. B of a salt thereof, is used.
  • Salts of compounds I can be prepared in a manner known per se. So get For example, acid addition salts of compounds I by treatment with a suitable acid or a suitable ion exchange reagent and salts with bases by treatment with a suitable base or a suitable ion exchange reagent. Salts of compounds of formula I can in the usual way in the free compounds I are converted, acid addition salts z. B. by treating with a suitable basic agent or a suitable ion exchange reagent and salts with bases z. By treatment with a suitable acid or ion exchange reagent.
  • Salts of compounds I can be prepared in a manner known per se into other salts of compounds I acid addition salts, for example in other acid addition salts, z.
  • a salt of an organic acid such as a hydrochloride
  • a suitable metal salt such as a sodium, barium, or silver salt
  • a Acid e.g. As silver acetate
  • a suitable solvent in which a forming organic salt, e.g. As silver chloride, insoluble and thus from the reaction mixture excretes.
  • the compounds I with salt-forming Properties are obtained in free form or in the form of salts.
  • the compounds I including their salts of salt-forming compounds also be obtained in the form of their hydrates and / or others, for example, if appropriate used for the crystallization of compounds present in solid form, solvents lock in.
  • the compounds I and their salts can, depending on the choice of starting materials and procedures, in the form of one of the possible isomers, for example stereoisomers or tautomers, or as a mixture thereof.
  • isomers z. B pure enantiomers, pure diastereoisomers or pure tautomers available.
  • Isomer mixtures z. B. racemates or diastereoisomeric mixtures.
  • the invention also relates to compounds of the formula I and their pharmaceutically acceptable Salts for the treatment of diseases that contain excess iron in the human or cause or be caused by it, preferably in the form of pharmaceutically acceptable preparations, in particular in a process for the therapeutic treatment of the human body, and such a treatment method.
  • the invention also relates to pharmaceutical preparations containing a compound I or a pharmaceutically acceptable salt thereof as the active ingredient, and methods for their use Production.
  • These pharmaceutical preparations are those for enteral, especially oral, rectal, and parenteral administration Administration to warm-blooded animals, especially to humans, with the pharmacological agent is contained alone or together with conventional pharmaceutical excipients.
  • the pharmaceutical preparations (in weight percent) z. From about 0.001% to about 100%, preferably from about 0.1% to about 100% of the active ingredient.
  • compositions for enteral or parenteral administration are z. B. such in unit dosage forms such as dragees, tablets, dispersible tablets, effervescent tablets, Capsules, suspendable powders, suspensions or suppositories, or ampoules. These be in a conventional manner, for. B. by conventional drageeing, mixing, granulating, or lyophilization process. So you can use pharmaceutical preparations for oral application by combining the active ingredient with solid excipients, a mixture obtained optionally granulated and the mixture or granules, if desired or necessary, after addition of suitable excipients, to tablets or Processed dragée kernels.
  • Suitable carriers are in particular fillers such as sugars, for. Lactose, sucrose, Mannitol, or sorbitol, cellulose preparations and / or calcium phosphates, e.g. B. tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes, using z. Of corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and or polyvinylpyrrolidone, and, if desired, disintegrants such as those mentioned above Starch, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for. Lactose, sucrose, Mannitol, or sorbitol, cellulose preparations and / or calcium phosphates, e.g. B. tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes, using
  • Dragee seeds are provided with appropriate, optionally gastric juice-resistant, provided coatings, where u. a. concentrated Sugar solutions which may be arabic gum, talc, polyvinylpyrrolidone, Polyethylene glycol and / or titanium dioxide, paint solutions in suitable organic Solvents or solvent mixtures or for the production of gastric juice-resistant Coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethyl cellulose phthalate.
  • the tablets or dragee covers For example, dyes or pigments, e.g. For identification or identification different doses of active substance, to be attached.
  • Dispersible tablets are in a relatively small amount of liquid, z.
  • Other orally applicable Pharmaceutical preparations are gelatine capsules and soft, closed ones Capsules of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the Capsules may contain the active ingredient in the form of granules, eg. B.
  • soft capsules in admixture with fillers, such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally Stabillisatoren included.
  • fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally Stabillisatoren included.
  • suitable liquids such as fatty oils, paraffin oil or liquid Polyethylene glycols, dissolved or suspended, stabilizers also being added can.
  • the active ingredient for example, with pharmaceutical applicable surface-active substances, such as sodium lauryl sulfate or Polysorbate, suspending aids, for example hydroxypropylcellulose, hydroxypropylmethylcellulose or another known from the prior art and, for example, in "Handbook of Pharmaceutical Excipients” above, pH regulators, such as lemon or Tartaric acid and its salts or a USP buffer and, optionally, fillers, z.
  • pharmaceutical applicable surface-active substances such as sodium lauryl sulfate or Polysorbate
  • suspending aids for example hydroxypropylcellulose, hydroxypropylmethylcellulose or another known from the prior art and, for example, in “Handbook of Pharmaceutical Excipients” above, pH regulators, such as lemon or Tartaric acid and its salts or a USP buffer and, optionally, fillers, z.
  • aqueous solutions of an active ingredient in water-soluble form e.g. B. a water-soluble salt
  • the active ingredient such as corresponding oily injection suspensions
  • suitable lipophilic Solvent or vehicle such as fatty oils, e.g. Sesamol, or synthetic fatty acid esters, z. Ethyl oleate or Tnglycende, or aqueous injection suspensions, which viscosity-increasing substances, for.
  • suitable lipophilic Solvent or vehicle such as fatty oils, e.g. Sesamol, or synthetic fatty acid esters, z. Ethyl oleate or Tnglycende
  • viscosity-increasing substances for example, sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally also stabilizers.
  • the dosage of the drug may depend on various factors, such as effectiveness and duration of action the active substance, the strength of the disease or symptoms to be treated, Mode of administration, warm-blooded species, sex, age, weight and / or individual Condition of the warm-blooded animal, hang out.
  • the doses to be administered daily are included oral administration between 10 and about 120 mg / kg, especially 20 and about 80 mg / kg and for a warm-blooded animal with a body weight of about 40 kg preferably between about 400 mg and about 4800 mg, in particular about 800 mg to 3200 mg, the expediently divided into 2 to 12 individual doses.
  • the same product can also be made as follows: 0.915 g of 2-benzyl-3-hydroxy-1- (2-acetoxy-ethyl) -1 H -pyridin-4-one (Example 42) are dissolved in a mixture of 2 ml of 2N NaOH and 10 ml of ethanol for 24 hours at room temperature touched. 2 ml of 2N HCl are then added and the mixture is stirred for one hour at room temperature. Filter and wash with cold ethanol. After drying, 2-benzyl-3-hydroxy-1- (2-hydroxy-ethyl) -1 H -pyridin-4-one.
  • Example 13b 3-benzyloxy-1- (2,3-dihydroxy-propyl) -2- (hydroxy-phenyl-methyl) -1 H -pyridin-4-one (Example 13b) is obtained analogously to Example 2: 2 -benzyl-1- (2,3-dihydroxy-propyl) -3-hydroxy-1 H -pyridin-4-one. Crystallization from methanol, mp: 185-186 ° C.
  • Example 17 4- ⁇ 2 - [(4-fluoro-phenyl) -hydroxy-methyl] -3-hydroxy-4-oxo-4 H -pyridin-1-yl ⁇ -butyric acid
  • Example 18 ⁇ 2 - [(4-fluoro-phenyl) -hydroxy-methyl] -3-hydroxy-4-oxo-4 H -pyridin-1-yl ⁇ acetic acid
  • the same product can also be made as follows: 1.2 g of 3-benzyloxy-1- (2-hydroxy-ethyl) -2- [hydroxy (4-bromo-phenyl) methyl] -1 H -pyridin-4-one with 12 ml of HCl conc. 37% poured over and heated to 110 ° C with stirring for 10 minutes. Cool and add 15 g of ice. With stirring and cooling in an ice bath neutralized with sodium hydroxide solution until pH 6.5 is reached. It sets 15 ml of ethyl acetate and allowed to stir at room temperature for 18 hours. The precipitated product is filtered off and washed with water and ethyl acetate. After Umknstallisation from ethanol to obtain 2 - [(4-bromo-phenyl) -hydroxy-methyl] -3-hydroxy-1- (2-hydroxy-ethyl) -1 H -pyridin-4-one.
  • Example 35 1- (4-chloro-phenyl) -9-hydroxy-3,4-dihydro-1 H -pyrido [2,1-c] [1,4] oxazin-8-one
  • Example 36 1- (4-fluoro-phenyl) -9-hydroxy-3,4-dihydro-1 H -pyrido [2,1-c] [1,4] oxazin-8-one
  • Example 37 1- (4-bromo-phenyl) -9-hydroxy-3,4-dihydro-1 H -pyrido [2,1-c] [1,4] oxazin-8-one
  • Example 38 6 - [(4-Fluoro-phenyl) -hydroxy-methyl] -7-hydroxy-3,4-dihydro-pyrido [2,1-c] [1,4] oxazine-1,8-dione
  • Example 32e From 0.46 g of 3-benzyloxy-1- (2-hydroxy-ethyl) -2- (hydroxy-p-tolyl-methyl) -1 H -pyridin-4-one (Example 32e) is obtained analogously to Example 35: 9 -hydroxy-1-p-tolyl-3,4-dihydro-1 H -pyrido [2,1-c] - [1,4] oxazin-8-one. Reddish crystals, mp: 210-218 ° C with decomposition. Crystal transformation of rods in needles from 200 ° C.
  • the starting material can be prepared, for example, as follows: a) Acetic acid [1- (2-acetoxy-ethyl) -3-benzyloxy-4-oxo-1,4-dihydropyridin-2-ylmethyl] -phenyl-methyl ester: 1.76 g of 3-benzyloxy-1-one (2-hydroxy-ethyl) -2- (hydroxy-phenyl-methyl) -1 H -pyridin-4-one (example 1d) are suspended in 20 ml of dichloromethane, and 1.5 ml of triethylamine.
  • Example 43 Acetic acid [1- (2-acetoxy-ethyl) -3-hydroxy-4-oxo-1,4-dihydropyridin-2-ylmethyl] -phenyl-methyl ester
  • the starting material can be prepared, for example, as follows: a) Acetic acid [1- (2-acetoxy-ethyl) -3-benzyloxy-4-oxo-1,4-dihydropyridin-2-ylmethyl] -phenyl-methyl ester: 17.4 g of 3-benzyloxy-1- (2 -hydroxy-ethyl) -2- (hydroxy-phenyl-methyl) -1 H -pyridin-4-one (example 1d) are suspended at room temperature in 200 ml of dichloromethane. 33 ml of triethylamine and 18.7 ml of acetic anhydride are added.
  • Example 44 4- ⁇ 2 - [(4-fluoro-phenyl) -hydroxy-methyl] -3-hydroxy-4-oxo-4 H -pyridin-1-yl ⁇ -butyric acid ethyl ester
  • Example 45 4- [3-hydroxy-2- (hydroxy-phenyl-methyl) -4-oxo-4 H -pyridin-1-yl] -buttersaureethylester
  • Example 48 1- (4-fluorophenyl) -3,9-dihydroxy-3,4-dihydro-1 H -pyrido [2,1-c] [1,4] oxazin-8-one
  • Example 50 2 - [(3-fluorophenyl) -hydroxy-methyl] -3-hydroxy-1- (2-hydroxy-ethyl) -1 H -pyridin-4-one
  • Example 54 Acetic acid 1- (2-acetoxy-ethyl) -6- [acetoxy- (4-fluoro-phenyl) -methyl] -5-hydroxy-4-oxo-1,4-dihydro-pyridin-2-ylmethyl ester
  • Example 58 4- (3-hydroxy-naphth-2-ylmethyl-4-oxo-4 H -pyridin-1-yl) -butyric acid ethyl ester
  • Example 60 4- ⁇ hydroxy- [3-hydroxy-1- (2-hydroxy-ethyl) -4-oxo-1,4-dihydro-pyridin-2-yl] -methyl ⁇ -benzonitrile
  • Example 81 Acetic acid 2- [3-hydroxy-2- (4-chlorobenzyl) -4-oxo-4H-pyridin-1-yl] -ethyl ester
  • Example 83 Acetic acid [1- (2-acetoxy-ethyl) -3-hydroxy-4-oxo-1,4-dihydropyridin-2-yl] - (2-fluorophenyl) -methyl ester
  • Example 84 Acetic acid 2- [3-hydroxy-2- (3-fluorobenzyl) -4-oxo-4H-pyridin-1-yl] -ethyl ester
  • Example 84 From 0.702 g of acetic acid 2- [3-hydroxy-2- (3-fluorobenzyl) -4-oxo-4H-pyridin-1-yl] ethyl ester (Example 84) is obtained analogously to Example 72 3-hydroxy-1- (2 -hydroxy-ethyl) -2- (3-fluoro-benzyl) - 1H -pyridin-4-one as colorless crystals, mp: 235-242 ° C, slow decomposition from 204 ° C.
  • active ingredient is a compound of the formula in free Form or in the form of a pharmaceutically acceptable salt, in particular such a compound described as a product in any of the preceding examples is.
  • Example A Tablets each containing 200 mg of active ingredient can be prepared as follows:
  • composition (10000 tablets) active substance 2000.0 g lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g Silica (highly dispersed) 20.0 g ethanol q.s.
  • the active ingredient is mixed with the lactose and 292 g of potato starch, the mixture with an ethanolic solution of gelatin moistened and granulated by a sieve Drying mixes the rest of the potato starch, the magnesium stearate, the talc and the silica to and pressed the mixture into tablets of 295.0 mg each weight and 200 mg of active ingredient, if desired with partial scores for finer adjustment the dosage can be provided.
  • Example B Lacquered tablets, each containing 400 mg of active ingredient, can be prepared as follows.
  • composition 1000 tablets
  • the active substance, lactose and 40 g of maize starch are mixed and mixed with a paste, prepared from 15 g of corn starch and water (with heating), moistened and granulated.
  • the granules are dried, the rest of the corn starch, the talc and the calcium stearate added and mixed with the granules.
  • the mixture is compressed into tablets and this with a solution of hydroxypropyl methylcellulose and shellac in Dichloromethane lacquered; Final weight of the coated tablet: 583 mg.
  • Example C Gelatin capsules containing 500 mg of active ingredient may e.g. B. be prepared as follows:
  • Composition for 1000 capsules:
  • lactose 250.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate 2.0 g magnesium stearate 8.0 g
  • the sodium lauryl sulfate is passed through a sieve with a mesh size of 0.2 mm to the lyophilised active substance added. Both components are intimately mixed. then First, the lactose through a sieve with a mesh size of 0.6 mm and then the microcrystalline cellulose through a sieve with a mesh size of 0.9 mm. then again 10 minutes intimately mixed. Finally, the magnesium stearate is through a sieve with a mesh size of 0.8 mm is added. After 3 minutes further mixing each 790 mg of the resulting formulation in Gelatinesteckkapseln suitable Size bottled.
  • Example D Oral suspension powder containing 300 mg of active ingredient can be prepared, for example, as follows
  • Hydroxypropylcellulose (Klucel HF) 50 mg tartaric acid 100 mg sodium lauryl sulfate 100 mg
  • the sodium lauryl sulfate is passed through a sieve with a mesh size of 0.2 mm to the lyophilised active substance added. Both components are intimately mixed. Then the microcrystalline cellulose is passed through a sieve with a mesh size of 0.9 mm. Then it is mixed again for 10 minutes. Finally, the tartaric acid is through a sieve with a mesh size of 0.8 mm is added. After 3 minutes further mixing The mixture is filled into a vessel of at least 10 ml capacity For use, make up to 10 ml with water and shake the mixture vigorously.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Toxicology (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pyrane Compounds (AREA)
EP96810622A 1995-09-29 1996-09-20 Hydroxypyridinone Expired - Lifetime EP0768302B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SA96170399A SA96170399B1 (ar) 1995-09-29 1996-10-30 مركبات جديدة من هيدوركس بيريدينونات hydroxypyridinones

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH275995 1995-09-29
CH275995 1995-09-29
CH2759/95 1995-09-29

Publications (3)

Publication Number Publication Date
EP0768302A2 EP0768302A2 (de) 1997-04-16
EP0768302A3 EP0768302A3 (de) 1998-02-25
EP0768302B1 true EP0768302B1 (de) 2005-07-06

Family

ID=4240981

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96810622A Expired - Lifetime EP0768302B1 (de) 1995-09-29 1996-09-20 Hydroxypyridinone

Country Status (22)

Country Link
US (1) US5688815A (cs)
EP (1) EP0768302B1 (cs)
JP (1) JPH09124603A (cs)
KR (1) KR970015576A (cs)
CN (1) CN1151399A (cs)
AR (1) AR005419A1 (cs)
AT (1) ATE299135T1 (cs)
AU (1) AU6584596A (cs)
BR (1) BR9603929A (cs)
CA (1) CA2186716A1 (cs)
CZ (1) CZ284896A3 (cs)
DE (1) DE59611243D1 (cs)
ES (1) ES2244967T3 (cs)
HU (1) HUP9602681A1 (cs)
IL (1) IL119316A (cs)
MX (1) MX9604367A (cs)
NO (1) NO964095L (cs)
NZ (1) NZ299452A (cs)
PT (1) PT768302E (cs)
SA (1) SA96170399B1 (cs)
TR (1) TR199600765A2 (cs)
ZA (1) ZA968150B (cs)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8889877B2 (en) 2010-03-23 2014-11-18 Viiv Healthcare Company Processes for preparing pyridinone carboxylic acid aldehydes

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9711093D0 (en) 1997-05-29 1997-07-23 British Tech Group Novel orally active iron (III) chelators
US6448273B1 (en) 1997-05-29 2002-09-10 Btg International Limited Orally active iron (III) chelators
GB9723078D0 (en) * 1997-10-31 1998-01-07 Cerebrus Ltd Chemical compounds
JPH11147377A (ja) * 1997-11-18 1999-06-02 Teijin Ltd 感熱転写リボン用二軸配向ポリエステルフィルム
US6767741B1 (en) * 1999-08-27 2004-07-27 Invitrogen Corporation Metal binding compounds and their use in cell culture medium compositions
DE60037819T2 (de) * 1999-08-27 2009-01-08 Invitrogen Corp., Carlsbad Metallbindende verbindungen und deren verwendung in zusammensetzungen für zellkulturmedien
US6846915B2 (en) 2001-08-13 2005-01-25 The Regents Of The University Of California Hydroxypyridonate and hydroxypyrimidinone chelating agents
US6426418B1 (en) 2001-11-02 2002-07-30 Apotex, Inc. Processes for the manufacturing of 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide
PL371746A1 (en) 2002-02-05 2005-06-27 Bristol-Myers Squibb Company N-substituted3-hydroxy-4-pyridinones and pharmaceuticals containing thereof
US20050008699A1 (en) * 2003-07-11 2005-01-13 Fred Wehling Effervescent glucosamine composition
NZ529657A (en) * 2003-11-20 2004-07-30 Apotex Inc Iron chelating cycloalkyl derivatives of 3-hydroxy-4-pyridinones
CA2488034C (en) * 2004-11-19 2009-10-06 Apotex Inc. Process for the manufacture of 3-hydroxy-n-alkyl-1-cycloalkyl-6-alkyl-4-oxo-1,4-dihydropyridine-2-carboxamide and its related analogues
GB0506677D0 (en) * 2005-04-01 2005-05-11 Btg Int Ltd Iron modulators
WO2010011814A1 (en) 2008-07-25 2010-01-28 Smithkline Beecham Corporation Chemical compounds
WO2010019924A1 (en) * 2008-08-15 2010-02-18 Burnham Institute For Medical Research Composition and methods for the design and development of metallo-enzyme inhibitors
CN102245572B (zh) * 2008-12-11 2015-03-25 盐野义制药株式会社 氨甲酰基吡啶酮hiv整合酶抑制剂的方法和中间体
KR101733625B1 (ko) 2008-12-11 2017-05-10 시오노기세야쿠 가부시키가이샤 카르바모일피리돈 ｈｉｖ 인테그라제 억제제 및 중간체의 합성
TWI518084B (zh) 2009-03-26 2016-01-21 鹽野義製藥股份有限公司 哌喃酮與吡啶酮衍生物之製造方法
CN101906069B (zh) * 2009-06-02 2012-12-12 首都医科大学 (s)-2-取代-(3＇-乙酰基-2＇-吡啶酮-1＇-基)乙酸及其制备方法和应用
GEP20146008B (en) * 2009-07-03 2014-01-10 Apotex Tech Inc Fluorinated derivatives of 3-hydroxypyridin-4-ones
CN103118973B (zh) * 2010-07-27 2016-03-23 科莱恩金融(Bvi)有限公司 羟基吡啶酮或其盐用于稳定化过氧化氢或释放过氧化氢的物质的用途
CN105017138A (zh) * 2015-08-06 2015-11-04 中国科学技术大学 一种乙二醇化3-羟基吡啶-4-酮类化合物及其制备方法和用途
CN110790737B (zh) * 2019-11-07 2022-07-22 河南中烟工业有限责任公司 一种2,3-二氢-3,5-二羟基-6-乙基-4h-吡喃-4-酮的制备方法
CN118496186B (zh) * 2024-05-14 2025-09-02 海南师范大学 一种吡喃酮衍生物及其制备方法与应用
CN119977990B (zh) * 2024-12-30 2026-03-31 海南师范大学 一种海洋真菌来源的杀虫杀菌化合物及其制备方法

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1518098A1 (de) * 1963-09-19 1969-04-10 Pfizer & Co C Verfahren zur Herstellung von Pyromekonsaeurederivaten
GB2118176B (en) * 1982-03-24 1985-12-04 Nat Res Dev Pharmaceutical compositions
GB8308054D0 (en) * 1983-03-24 1983-05-05 Hider R C Pharmaceutical compositions
US4908371A (en) * 1987-11-10 1990-03-13 Ciba-Geigy Corporation Esterified hydroxy dihydropyridinones for treating diseases associated with trivalent metal ion overload
EP0325559B1 (de) * 1988-01-20 1993-12-15 Ciba-Geigy Ag Verfahren zur Herstellung von Komplexverbindungen
WO1989009211A1 (en) * 1988-03-31 1989-10-05 The Royal Free Hospital School Of Medicine Process for producing pyrid-4-ones
US4980371A (en) * 1988-12-21 1990-12-25 Merrell Dow Pharmaceuticals Antiretroviral furan ketones
US5112968A (en) * 1989-07-28 1992-05-12 E. R. Squibb & Sons, Inc. Monobactam hydrazide derivatives
GB9100465D0 (en) * 1991-01-09 1991-02-20 Hider Robert C Pharmaceutical compositions
GB9209078D0 (en) * 1992-04-27 1992-06-10 Hider Robert C Pharmaceutical compositions
CA2100623A1 (en) * 1992-07-17 1994-01-18 Michiyuki Sendai Cephem compounds, their production and use
GB9216506D0 (en) * 1992-08-04 1992-09-16 Rice Evans Catherine A Improvements in or relating to the treatment of sickle cell disease
GB9217099D0 (en) * 1992-08-12 1992-09-23 British Tech Group Pharmaceutical compositions
US5789426A (en) * 1995-01-20 1998-08-04 Cornell Research Foundation, Inc. Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8889877B2 (en) 2010-03-23 2014-11-18 Viiv Healthcare Company Processes for preparing pyridinone carboxylic acid aldehydes
US9120817B2 (en) 2010-03-23 2015-09-01 Viiv Healthcare Company Process for preparing (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′ ,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid
US9643981B2 (en) 2010-03-23 2017-05-09 Viiv Healthcare Company Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12A-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
US10174051B2 (en) 2010-03-23 2019-01-08 Viiv Healthcare Company Substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US10647728B2 (en) 2010-03-23 2020-05-12 Viiv Healthcare Company Process for preparing (3S,11aR)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid
US10654870B2 (en) 2010-03-23 2020-05-19 Viiv Healthcare Company Process for preparing substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US10654871B2 (en) 2010-03-23 2020-05-19 Viiv Healthcare Company Process for preparing (3S,11aR)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

Also Published As

Publication number Publication date
EP0768302A3 (de) 1998-02-25
CZ284896A3 (en) 1997-04-16
ZA968150B (en) 1997-04-01
AR005419A1 (es) 1999-06-23
KR970015576A (ko) 1997-04-28
ES2244967T3 (es) 2005-12-16
PT768302E (pt) 2005-11-30
CA2186716A1 (en) 1997-03-30
JPH09124603A (ja) 1997-05-13
AU6584596A (en) 1997-04-10
HUP9602681A1 (en) 1997-09-29
NO964095L (no) 1997-04-01
IL119316A0 (en) 1996-12-05
DE59611243D1 (de) 2005-08-11
MX9604367A (es) 1997-10-31
HU9602681D0 (en) 1996-11-28
CN1151399A (zh) 1997-06-11
NO964095D0 (no) 1996-09-27
NZ299452A (en) 1998-06-26
IL119316A (en) 2000-08-13
EP0768302A2 (de) 1997-04-16
BR9603929A (pt) 1998-06-09
SA96170399B1 (ar) 2007-01-20
TR199600765A2 (tr) 1997-05-21
ATE299135T1 (de) 2005-07-15
US5688815A (en) 1997-11-18

Similar Documents

Publication Publication Date Title
EP0768302B1 (de) Hydroxypyridinone
DE69722858T2 (de) Intimale verdickungsinhibitoren
DE29724281U1 (de) 4-Phenylpiperidin-Verbindungen
DE69330282T2 (de) Chinolon und acridinon derivate zur behandlung der harninkontinenz
JP2002500663A (ja) 新規な経口用で活性な鉄（ｉｉｉ）キレート化剤
DE2065636A1 (de) Neue tricyclische verbindungen
DE2002840A1 (de) 2,3,5-trisubstit,-2'-Hydroxy-6,7-benzomorphane und Verfahren zu deren Herstellung
DE2162011C3 (de) 2-Phenyl-3-(4-methyl-piperazinocarbonyloxy)-1-isoindolinon-derivate, ihre Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
EP0410208B1 (de) Chromanderivate
DE3232462A1 (de) 2-nitro-1,1-ethendiamine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
DE2539907A1 (de) 4a-aryl-cis-decahydroisochinoline und diese verbindungen enthaltende arzneimittel
DE3309655A1 (de) 1,2,5-thiadiazol-1-oxide und 1,1-dioxide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE3835011A1 (de) Chromanderivate
DE2337068A1 (de) 1-benzylindenylsaeuren
DE3014813A1 (de) 2-hydroxy-5-(1-hydroxy-2-piperazinylethyl)benzoesaeure-derivate
DE2852088A1 (de) Substituierte pyrrolidine, verfahren zu ihrer herstellung, ihre verwendung und sie enthaltende arzneimittel
CH637132A5 (de) Verfahren zur herstellung neuer piperidylidenderivate von benzoxanthenen, -thioxanthenen und -dibenzoxepinen.
CH616935A5 (en) Process for the preparation of chromone derivatives
DE1470314A1 (de) Verfahren zur Herstellung von 5-substituierten Aza-Dibenzo-Cycloheptenen
DE69000224T2 (de) Thioformamidderivate.
DE1620151B1 (de) 10-Piperazino-dibenzo(a,d)cycloheptadienderivate und Verfahren zu ihrer Herstellung
CH621114A5 (en) Process for the preparation of 10,11-dihydro-3-carboxy- cyproheptadine and its N-oxide
EP0064026B1 (de) Neue dioxaheterocyclische Verbindungen, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
DE2642598A1 (de) Neue isoindolinderivate, deren herstellung und diese enthaltende zusammensetzungen
AT360990B (de) Verfahren zur herstellung des neuen 1-methyl-4- (3-carboxy-10,11-dihydro-5h-dibenzo-(a,d)- -cyclohepten-5-yliden)-piperidin (10,11-dihydro -3-carboxy-cyproheptadin), seines n-oxids und seiner salze

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

17P Request for examination filed

Effective date: 19980720

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NOVARTIS-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT M.B.

Owner name: NOVARTIS AG

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NOVARTIS-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT M.B.

Owner name: NOVARTIS AG

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NOVARTIS PHARMA GMBH

Owner name: NOVARTIS AG

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: NOVARTIS PHARMA GMBH

Owner name: NOVARTIS AG

17Q First examination report despatched

Effective date: 20030217

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20050706

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20050706

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)

Effective date: 20050707

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: GERMAN

REF Corresponds to:

Ref document number: 59611243

Country of ref document: DE

Date of ref document: 20050811

Kind code of ref document: P

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20050930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20051006

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20050402928

Country of ref document: GR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2244967

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: IE

Ref legal event code: FD4D

ET Fr: translation filed
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20060407

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20110913

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20120919

Year of fee payment: 17

Ref country code: SE

Payment date: 20120911

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20120817

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20120912

Year of fee payment: 17

Ref country code: IT

Payment date: 20120915

Year of fee payment: 17

Ref country code: FR

Payment date: 20120926

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20120321

Year of fee payment: 17

Ref country code: BE

Payment date: 20120912

Year of fee payment: 17

Ref country code: NL

Payment date: 20120908

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20121004

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20120829

Year of fee payment: 17

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 59611243

Country of ref document: DE

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20140320

BERE Be: lapsed

Owner name: *NOVARTIS A.G.

Effective date: 20130930

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20140401

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130921

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 299135

Country of ref document: AT

Kind code of ref document: T

Effective date: 20130920

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20050402928

Country of ref document: GR

Effective date: 20140403

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20130920

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 59611243

Country of ref document: DE

Effective date: 20140401

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20140530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140320

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130930

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130920

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130930

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130930

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140401

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140403

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130930

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130920

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140401

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130920

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20141007

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130921